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5-Benzyl and 5-benzyloxybenzyl-substituted 3′-azido-2′,3′-dideoxyuridine, (8a and 8b), 3′-halogeno-2′,3′-dideoxyuridine, 9a, 9b, 10a, 10b, 11a and 11b, and 2′,3′-dideoxyuridine, 12a and 12b, of Scheme I were synthesized as potential anti AIDS agents. Synthesis of epimers of 8a and 8b, 5-benzyl- and 5-benzyloxybenzyl-1-(3′-azido-2′,3′-dideoxy-β-D-threo-pentafuranosyl)uracil, 15a and 15b, and 5-benzyl- and 5-benzyloxy-5′-azido-2′,5′-dideoxyuridine, 16a and 16b, shown in Scheme II, were also reported.

1'-Halogenomethyl, 1'-azidomethyl and 1'-disubstituted aminomethyl derivatives of BAU (5-benzylacyclouridine) and BBAU (5-benzyloxybenzylacyclouridine) were synthesized in the course of our studies of benzylacyclouridines. Two new and more convenient preparations of the previously known aminomethyl-and hydroxyymethyl-parent compounds of these two series, AM-BAU, AM-BBAU and HM-BBAU are also reported. These compounds were synthesized during a search for potential antiviral agents and pyrimidine phosphorylase inhibitors

6-Arylthio and 6-arylselenoacyclonucleosides was synthesized and tested for the ability to inhibit replication of HIV-1. Lithiation of acyclonucleosides with LDA followed by reaction with the electrophiles phenyl disulfide, diphenyl diselenide, 2,2′-dipyrdyl disulfide or 2,2′-dipyridyl diselenide afforded 6-(arylthio or arylseleno)acyclonucleosides 5a-c, 6, 7, 9, 15a-c, 17a-c. Compounds 19a-c and 20a-c were obtained by deprotection of corresponding TBDMS derivatives. Dehydrated products 16a, and 18a-c were also formed during the reactions. 5-Ethyl-6-(α-pyridylthio or α-pyridylseleno) disubstituted acyclouracils 6 and 7 were more active against HIV-1 in both MT-2 and CEM-IW cell lines than AZT, DDC, DDI or D4T. The EC50 of 6 against HIV-1 in CEM-IW cell was in the nanomolar range with a therapeutic index of 1100.

A novel class of nucleosides with the C1, atom bonded to three hetero atoms was synthesized. 2′-Thia-2′,3′-dideoxycytidine was the pilot compound of this series. (±)-β-2′-Thia-1′,3′-dideoxycytidine (6) and (±)-α-2′-thia-2′,3′-dideoxycytidine (7) were synthesized from (±)-3-mercapto-1,2-propanediol. The synthesis of the enantiomerically pure 2′-thia-2′,3′-dideoxycytidines (α-D-form, β-D-form, α-1-form and β-L-form) from optically pure (S)-(2,2-dimethyl-1,3-dioxalan-yl)methyl p-toluenesulfonate (8) and its (R)-isomer 18 was also described. The preliminary biological results showed that (+)-β-D-2′-thia-2′,3′-dideoxycytidine (26) was the most active against human hepatitis B virus with an ED50 of 3 μM.

Amino analogs of BAU (5-benzylacyclouridine) and BBAU (5-benzyloxybenzylacyclouridine) and their 2′-hydroxymethyl derivatives were synthesized for evaluation as inhibitors of uridine phosphorylase and hence potential cancer chemotherapeutic agents. Both aminomethyl analogs were found to be potent inhibitors of this enzyme and good potentiators of the anti-tumor action of FUdR.

Racemic 2′-aminomethyl-5-benzyl-acyclouridine (AM-BAU, 5) and 2′-aminomethyl-5-benzyloxybenzyla-cyclouridine (AM-BBAU, 6) have been found to be very active inhibitors of uridine phosphorylase [1]. Their enantiomers were synthesized from chiral 2,2-dimethyl-1,3-dioxolane-4-methanol (7a,b). S-(—)-AM-BAU (5a) and S-(—)-AM-BBAU (6a) were prepared from the R-(—) isomer 7a, and R(+)-AM-BAU (5b) and R-(+)-AM-BBAU (6b) from the S-(+) isomer 7b. A different route from the S-(+) isomer 7b to S-(—)-AM-BBAU (6a) was also determined to be feasible.